The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature.

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.

Improvement of medical judgments by numerical training in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: People with multiple sclerosis (MS) have to face important decisions with regard to their medical treatment. The aim of this study was to evaluate whether a targeted cognitive training reduces framing effects and thus improves medical judgments. METHODS: This was a randomized, double-blind, cross-over study enrolling patients with relapsing-remitting MS and healthy controls (HCs). Participants were randomly assigned to training order A (first week, numerical training; second week, control training) or B (reverse order). The primary endpoint was changed in a framing task score (framing effect). In the framing task, participants evaluated the success of fictive medications on a 7-point scale. Medications were described in either positive or negative terms. RESULTS: A total of 37 patients and 73 HCs performed either training order A (n = 56) or B (n = 54). The framing effect decreased after the numerical training regardless of training order. No such decrease was found after the control training. Mean change in framing effect was -0.3 ± 0.8 after the numerical training and 0.03 ± 0.6 after the control training. This specific effect of training type was comparable between groups. CONCLUSION: Judgments of medical information improve in both patients with relapsing-remitting MS and HCs after a targeted numerical training. Thus, a specific cognitive intervention may help patients making informed decisions.

A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type.

Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.

[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society]. / Konsensusstatement "Demenz 2010" der Osterreichischen Alzheimer Gesellschaft.

The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.

Hippocampal abnormalities in malformations of cortical development: MRI study.

OBJECTIVES: Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities. METHODS: Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 +/- 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%). RESULTS: Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%]). CONCLUSIONS: About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.

Neuroscience of learning arithmetic--evidence from brain imaging studies.

It is widely accepted that the human brain is remarkably adaptive not only in child development, but also during adulthood. Aim of this work is to offer an overview and a systematic analysis of neuroimaging studies on the acquisition of arithmetic expertise. In normally developing children and adults, the gain of arithmetic competence is reflected by a shift of activation from frontal brain areas to parietal areas relevant for arithmetic processing. A shift of activation is also observed within the parietal lobe from the intraparietal sulci to the left angular gyrus. Increases in angular gyrus activation with gaining of expertise have also been documented in other cognitive domains. It appears that the left angular gyrus activation is modulated by inter-individual differences in arithmetic performance. The comparison of normal individuals with exceptionally performing individuals (e.g., calculating prodigies) suggests that the experts' arithmetic proficiency relies on a more extended activation network than the network found in non-experts. In expert individuals with long-lasting, extensive mathematical training, specific structural brain modifications are also evident.

Decision making under risk and under ambiguity in Parkinson's disease.

In the present study we investigate decision making under ambiguity and decision making under risk in Parkinson's disease (PD) patients without cognitive impairment and in patients affected by Parkinson's disease dementia (PDD). In decisions under ambiguity, participants are not aware of the rules for gains and losses and have to learn about the utility of their selections through feedback. The two patient groups showed significant deficits and did not differ in the frequency of advantageous choices, though they had a markedly different cognitive profile. In decisions under risk, explicit information on the options' probabilities as well as on the associated gains and losses is given. PD patients and healthy controls performed at the same level, whereas PDD patients made significantly more risky and disadvantageous decisions. Results of the study suggest that both patient groups are impaired in decision making when learning by feedback and emotional processing is required, while only the PDD group shows difficulties when decision making is based on cognitive reasoning strategies.

Numerical deficits in a single case of basal ganglia dysfunction.

The present investigation assesses specific numerical difficulties in a patient (SJ) with basal ganglia (BG) dysfunction. While previous studies on number processing in BG disorders typically tested arithmetic facts by production tasks, the present study uses production, recognition (verification, multiple-choice) and indirect (number-matching) arithmetic tasks. Patient SJ was severely impaired in production and to a lesser extent in verification and multiple-choice tasks. In number-matching, an abnormal latency pattern was found. This study extends previous research by indicating that BG dysfunction may not only affect production processes and sequencing, as was found in previous investigations, but may lead to a breakdown of semantic relationships of arithmetic facts.

Impact of ambiguity and risk on decision making in mild Alzheimer's disease.

Decisions under ambiguity and decisions under risk are crucial types of decision making in daily living at any age. This is the first study assessing these two types of decisions in patients with mild dementia of Alzheimer's type (DAT) by means of the Iowa Gambling Task (IGT) and a newly developed, Probability-Associated Gambling (PAG) task. While rules for gains and losses are implicit in the IGT, in the PAG task rules are explicit and winning probabilities, which change from trial to trial, can be estimated. Results of the IGT indicated that DAT patients made more disadvantageous decisions than healthy controls. Patients also shifted more frequently among decks, i.e. under ambiguity decisions were taken randomly and no advantageous strategy was established over time by DAT patients. Thus, not only actual choices but also development of advantageous strategies may be revealing about decision making in the IGT. Compared to controls, patients demonstrated less advantageous choices in the PAG task as well. They gambled more often in the low winning probabilities and less frequently in the high probabilities than healthy participants. Patients' performance on both tasks correlated with measures of executive functions. Findings of the present investigation are consistent with the early pathological cerebral changes and related (cognitive, emotional) deficits reported for DAT. As suggested by our study, decisions under ambiguity as well as decisions under risk are impaired in mild DAT. It may thus be expected that patients with mild DAT have difficulties in taking decisions in every-day life situations, both in cases of ambiguity (information on probability is missing or conflicting, and the expected utility of the different options is incalculable) and in cases of risk (outcomes can be predicted by well-defined or estimable probabilities).

Decision-making with explicit and stable rules in mild Alzheimer's disease.

Decision-making in mild dementia of Alzheimer's type (DAT) was assessed in a gambling task with stable and explicit rules [Game of Dice Task; Brand, M., Labudda, K., Kalbe, E., Hilker, R., Emmans, D., Fuchs, G., et al. (2004). Decision-making impairments in patients with Parkinson's disease. Behavioural Neurology, 15, 77-85]. DAT patients in an early stage of the disease chose safe alternatives as frequently as healthy elderly persons and did not show risky behaviour as has been reported for other neurological patient groups. However, a more detailed analysis disclosed important differences between DAT and healthy elderly. Compared to healthy controls, DAT patients shifted more frequently between safe and risky alternatives and showed less consistent response patterns. Frequent changes between strategies indicate that decisions were taken randomly, that no advantageous strategy was established and that no consistent response pattern was developed over time. As regards performance changes over the task, healthy participants had a stronger tendency towards safe and advantageous responses than DAT patients. While healthy controls showed learning as the task proceeded, DAT patients did not adapt their strategies. The proportion of "consistently safe responders" was significantly higher in the control group than in the DAT group. Analysis of reaction times indicated that differences in response behaviour were not due to fast and impulsive decision taking in the DAT group. DAT patients' response pattern may be attributed to deficits in learning and in executive functions. The frequency of changes between safe and risky choices proved to be a fair predictor for the distinction between mild DAT and healthy aging.

Effects of age and mild cognitive impairment on direct and indirect access to arithmetic knowledge.

The present study aimed at investigating age-related changes and mild cognitive impairment (MCI) related effects in simple arithmetic. To pursue this goal, MCI patients, healthy old adults and young adults performed three computerised tasks. The production (e.g., 3 x 4=?) and the verification task (3 x 4 12?) evaluated direct access to multiplication knowledge, the number-matching task (3 x 4 34?, 'do 3 x 4 and 34 have the same digits?') tested indirect access. In verification and number-matching, interference from related distractors (e.g., 3 x 4 followed by 16) relative to unrelated distractors (17) reflects access to stored fact representations as well as efficiency of inhibition processes. Results indicated that, compared to young adults, MCI and healthy old adults were slower in responding across tasks. In production and verification, analyses of individual latency regression slopes and intercepts suggested that these age effects were related to differences at peripheral processing stages (e.g., encoding) rather than at the central (arithmetic retrieval) stage. Differences between MCI and healthy elderly emerged only in the number-matching task. While in verification effects were comparable between groups, in number-matching MCI patients were more susceptible to interference from irrelevant information than healthy old participants. Overall, the present findings indicate that aging has a general effect on peripheral processing speed, but not on arithmetic memory retrieval. Parietal cortico-subcortical circuits mediating arithmetic fact retrieval (Dehaene, S., & Cohen, L. (1995). Towards an anatomical and functional model of number processing. Mathematical Cognition, 1, 83-120; Dehaene, S., & Cohen, L. (1997). Cerebral pathways for calculation: Double dissociation between rote verbal and quantitative knowledge of arithmetic. Cortex, 33, 219-250) thus seem to be preserved in normal aging and MCI. In contrast, MCI patients show enhanced interference in number-matching. This task-specific lack of inhibition may point to dysfunctional frontal cortico-subcortical networks in MCI.

Knowing 7 x 8, but not the meaning of 'elephant': evidence for the dissociation between numerical and non-numerical semantic knowledge.

Patients affected by semantic dementia (SD) and other severe cognitive deficits may show preserved numerical skills, including the retrieval of multiplication facts from long-term memory. No studies so far specifically investigated the network of arithmetic facts in semantic dementia. Thus, it is unknown whether preserved multiplication in SD truly reflects intact semantic knowledge or preserved retrieval of verbal sequences (just as the recitation of rhymes or poems). In the present study a patient (SG) with SD underwent an extensive assessment of number processing and calculation abilities. In particular, multiplication knowledge was investigated through a series of computerised tasks (production task, multiple-choice task, number bisection task with multiplicative triplets, number-matching task). SG demonstrated excellent performance in all number processing and calculation tasks. In computerised tasks tapping multiplication fact knowledge, SG was as accurate and fast as healthy controls. Analyses on individual regression slopes indicated that SG's reaction time effects (problem-size effect, problem-difficulty effect, interference effects, and facilitation effect) were comparable to those found in controls in each task. These results add new evidence to the independence of numerical knowledge from other semantic information and provide further insight into the organisation of stored arithmetic knowledge.

Number processing in posterior cortical atrophy--a neuropsycholgical case study.

Posterior cortical atrophy (PCA) is an uncommon syndrome of dementia with early onset, characterised by disorders of higher visual function, variable symptoms of Balint's syndrome, visual agnosia, alexia, agraphia, finger agnosia, right-left disorientation and dyscalculia [Benson D. F., Davis R. J., & Snyder B. D. (1988). Posterior cortical atrophy. Archives of Neurology, 45, 789-793]. In a single case study specific numerical deficits were observed which may be predicted by parietal neurodegeneration (more pronounced on the right side; verified by SPECT). Besides impairments in all tasks involving visuo-spatial abilities (e.g., dot counting, analog number scale task), deficits appeared in tasks requiring access to an internal representation of numbers such as mental number bisection, approximation, estimation and semantic facts. In number comparison an increased distance effect was found. In simple arithmetic, a striking dissociation between operations was found-multiplication and addition facts being preserved at a superficial level, subtraction and division being severely impaired. The study confirms the close relation between spatial and numerical processing and highlights the modular organisation of the semantic system (number semantics impaired). Moreover, the study adds evidence about the clinical manifestation of the particular degenerative syndrome.

[The clinical syndrome of posterior cortical atrophy]. / Das klinische Syndrom der posterioren kortikalen Atrophie.

Posterior cortical atrophy (PCA) is a syndrome that involves distinct neuropsychological deficits. This paper presents the clinical and neuropsychological findings recorded in four patients with PCA and reviews the characteristics of the syndrome and other conditions that need to be considered in the differential diagnosis. The cardinal symptoms of PCA are deficits of higher visual and spatial functions (mostly taking the form of Balint's syndrome), variably associated with disorders of visual perception, topographical disorientation, visual object agnosia and prosopagnosia, and deficits affecting reading, copying, drawing, and calculation. PCA is mostly associated with histopathological changes similar to those found in dementia of Alzheimer type (DAT), which are located predominantly in posterior brain regions. Memory and language functions tend to be preserved better and for a longer time in PCA than in the normal variant of DAT. SPECT and PET show deficits of perfusion and metabolism in both parietal and occipital lobes. The diagnosis of PCA is based on neuropsychological and imaging findings.

Cholinergic treatment of amnesia following basal forebrain lesion due to aneurysm rupture--an open-label pilot study.

Impairments of memory are often found after rupture and repair of aneurysms leading to a basal forebrain lesion. This open study investigated whether cholinergic substitution therapy may be a treatment option. The effect of donepezil, a cholinesterase inhibitor on memory functions was tested in an open-label, exploratory study in 11 patients with a chronic amnestic syndrome from a ruptured and repaired aneurysm of the anterior communicating artery (seven patients), the anterior cerebral (two) or the pericallosal artery (two). Mean time since onset was 75.4 months. Memory was evaluated at baseline and consecutively after 4 weeks of 5 mg donepezil daily, 8 weeks of 10 mg donepezil, and 4 weeks after drug discontinuation. Memory functions were assessed using the California Verbal Learning Test and compared with a matched group of normal, untreated controls. Tests of attention and of executive functions were also administered. Donepezil was well tolerated. Strong group effects were found at baseline and at all follow-up measurements showing profound impairments of memory functions in the patient group. Within patient statistics showed significant improvements of short and long delay free recall scores during the treatment period, both with 5 and 10 mg donepezil daily, whereas attentional and executive functions improved only non-significantly. Memory functions decreased after drug discontinuation. Repeated test administration in the control group also showed an increase of memory scores which was minor when compared with the performance change in the patient group. Donepezil may improve episodic memory functions in patients suffering from a chronic amnestic syndrome caused by rupture and repair of aneurysms of the anterior communicating, the anterior cerebral or the pericallosal artery. Future doubled-blind, placebo-controlled trials are warranted to confirm these findings.

Learning by strategies and learning by drill--evidence from an fMRI study.

The present fMRI study investigates, first, whether learning new arithmetic operations is reflected by changing cerebral activation patterns, and second, whether different learning methods lead to differential modifications of brain activation. In a controlled design, subjects were trained over a week on two new complex arithmetic operations, one operation trained by the application of back-up strategies, i.e., a sequence of arithmetic operations, the other by drill, i.e., by learning the association between the operands and the result. In the following fMRI session, new untrained items, items trained by strategy and items trained by drill, were assessed using an event-related design. Untrained items as compared to trained showed large bilateral parietal activations, with the focus of activation along the right intraparietal sulcus. Further foci of activation were found in both inferior frontal gyri. The reverse contrast, trained vs. untrained, showed a more focused activation pattern with activation in both angular gyri. As suggested by the specific activation patterns, newly acquired expertise was implemented in previously existing networks of arithmetic processing and memory. Comparisons between drill and strategy conditions suggest that successful retrieval was associated with different brain activation patterns reflecting the underlying learning methods. While the drill condition more strongly activated medial parietal regions extending to the left angular gyrus, the strategy condition was associated to the activation of the precuneus which may be accounted for by visual imagery in memory retrieval.

Subacute dementia and imaging correlates in a case of Fahr's disease.

We report a case of idiopathic bilateral basal ganglia calcinosis, or Fahr's disease (FD) in a 50 year old patient who developed rapidly progressive behavioural abnormalities and severe neuropsychological impairments, but no movement disorder. Neuropsychological deficits included a severe dysexecutive syndrome, anterograde amnesia, and attentional impairment. Neuropsychiatric features comprised apathy with intermittent disinhibition, anxiety, irritability, frequent mood changes, ritualistic and antisocial behaviour, and psychosis. Fluorodeoxyglucose positron emission tomography showed a massive reduction of glucose metabolism in the basal ganglia and the frontal brain. The observed abnormalities possibly result from a disruption of frontostriatal circuits, presumably at the basal ganglia level. This case indicates that FD may cause exclusively behavioural alterations and that the associated hypometabolism in certain frontal areas is closely related to the clinical picture.

Number processing in temporal lobe epilepsy.

BACKGROUND: Specific cognitive impairments have been found in association with mesial temporal lobe epilepsy (TLE), such as deficits in declarative memory or verbal abilities. No attention has been paid so far to possible deficits in number processing. OBJECTIVE: To investigate deficits in number processing in patients with TLE. METHODS: Numerical abilities were assessed in 28 right handed patients with medically intractable unilateral TLE and in a control group. RESULTS: No differences between patients and controls were found in analogue number processing with Arabic input, in a comparison task, or in simple addition and simple subtraction; however, there were significant group differences in tasks with verbal input, in simple division, in complex mental calculation, in a semantic knowledge task, and in conceptual tasks. Only minor differences were found between patients with right and left TLE. CONCLUSIONS: While numerical deficits may be expected in patients with left sided TLE, it is open for discussion why patients with right sided TLE also show numerical deficits.

Learning complex arithmetic--an fMRI study.

Aim of the present functional magnet resonance imaging (fMRI) study was to detect modifications of cerebral activation patterns related to learning arithmetic. Thirteen right-handed subjects were extensively trained on a set of 18 complex multiplication problems. In the following fMRI session, trained and untrained problems (closely matched for difficulty) were presented in blocked order alternating with a number matching task and a fact retrieval task. Importantly, left hemispheric activations were dominant in the two contrasts between untrained and trained condition, suggesting that learning processes in arithmetic are predominantly supported by the left hemisphere. Contrasting untrained versus trained condition, the left intraparietal sulcus showed significant activations, as well as the inferior parietal lobule. A further significant activation was found in the left inferior frontal gyrus. This activation may be accounted for by higher working memory demands in the untrained as compared to the trained condition. Contrasting trained versus untrained condition a significant focus of activation was found in the left angular gyrus. Following the triple-code model [Science 284 (1999) 970], the shift of activation within the parietal lobe from the intraparietal sulcus to the left angular gyrus suggests a modification from quantity-based processing to more automatic retrieval. The present study shows that the left angular gyrus is not only involved in arithmetic tasks requiring simple fact retrieval, but may show significant activations as a result of relatively short training of complex calculation.

Brain activation pattern during a verbal fluency test in healthy male and female volunteers: a functional magnetic resonance imaging study.

Sex differences in executive speech tasks, favoring women, have been noted in behavioral studies and functional imaging studies. In the present study ten female and ten male volunteers underwent functional magnetic resonance imaging in a conventional block design. All subjects were selected on the basis of high performance on the verbal fluency task. Regions of activation were detected after performance of a covert lexical verbal fluency task inside the scanner. Men and women who did not differ significantly in verbal fluency task performance showed a very similar pattern of brain activation. Our data argue against genuine between-sex differences in cerebral activation patterns during lexical verbal fluency activities when confounding factors like performance differences are excluded.